The long term goal of this research is to provide a better understanding of the factors involved in regulation of hepatic glycogen metabolism. Specifically, I will study the regulation of hepatic glycogen synthesis by glucocorticoids, insulin, and glucose and determine how the regulation of hepatic glycogenesis is altered by diabetes. I will study hepatic glycogenesis using the isolated perfused rat liver which has the advantage over in vivo preparations of allowing one to study direct effects of effector molecules on an organ or system without having to consider secondary effects on other systems. Glycogen synthesis will be examined by looking at the actions of effector molecules on tissue levels of glucose, glycogen, uridine diphosphoglucose, and glucose-6-phosphate, and by studying their effects on labelled substrate incorporation into glycogen. The enzymes which will be studied in this regard are glycogen synthetase, synthetase kinase (protein kinase), synthetase phosphatase (protein phosphatase), glycogen phosphorylase, adenyl cyclase, and cyclic AMP phosphodiesterase. An attempt will also be made to determine the involvement of the cyclic nucleotides, cyclic AMP and cyclic GMP, in the regulation of hepatic glycogenesis by these controlling factors. Also, this study should demonstrate for the first time whether the effect of glucocorticoids to increase hepatic glycogen is a direct effect or a secondary effect due to an increased substrate supply. Finally, we should be able to demonstrate how diabetes affects the regulation of hepatic glycogenesis.